This project consists of several overlapping comprehensive, multidisciplinary population-based cohort and/or case-control studies to quantify the association between cancer-causing viruses (oncoviruses) with linked cancers. The studies focus on the role of the role of immunological alteration, infection and risk for cancer, including BL, NHL, Hodgkin lymphoma, kaposi sarcoma, lung cancer, cervical cancer, head and neck cancer, testicular cancer, breast cancer, penile cancer, and gastric cancer. Biological specimens (peripheral blood, saliva, tumor tissues), when available, are used to measure load of infectious agents, including HIV, HTLV-I/-II, HCV, and KSHV, also called HHV8, genetic variation in viral agents or the host to characterize association of biomarkers with cancer. The Second Multicenter Hemophilia Cohort Study (MHCS-II) enrolled and completed prospective follow-up of more than 2500 HCV-exposed persons with hemophilia. A public website was established (https:mhcs-ii.rti.org) with background information and data analysis procedures. Progression of HIV to AIDS was shown to be associated with mitochondrial and Y chromosome DNA haplogroups and with variants in the APOBEC3B and IL10 genes. Likelihood of hepatitis B virus (HBV) clearance was associated with variants in IL10 and IL20, and likelihood of hepatitis C virus (HCV) clearance was associated with variants in IL18 and immunoglobulin GM alleles. A four-year case-control study of classic (non-AIDS) Kaposi sarcoma and KSHV infection throughout the island of Sicily (where cKS and KSHV are endemic) was completed. Classic KS risk was significantly reduced with current smoking, and it was significantly and independently increased with diabetes and use of corticosteroids. Classic KS also was increased with residential exposure chromic luvisols, a soil associated with volcanoes. People with HIV/AIDS are at markedly increased risk for Merkel cell carcinoma (MCC), a highly lethal neuroendocrine skin cancer in which a novel polyomavirus (MCPyV) was recently discovered by others. MCC tumors that had little or no detectable MCPyV DNA were found to have high expression of the retinoblastoma oncogene and worse prognosis, compared to MCC tumors with a high level of MCPyV. A consensus group was convened, reporting the state-of-the-art of MCC and MCPyV virology, epidemiology, molecular pathology, and clinical management. Among 395 NHL cases from Jamaica matched by age, sex, calendar-year and HTLV serostatus to 309 controls from the same population, decreased NHL risk was associated with polymorphisms in Interleukin 13 (IL13) Ex4+98A>G (rs20541) odds ratio (OR) AG/AA)=0.62, p=0.006, vascular cell adhesion molecule 1 (VACM1) Ex9+ 14G>A polymorphism (rs1041163) OR [CT] 0.77, OR [CC] 0.35, p for trend =0.007. The associations were stronger in analyses restricted to patients with adult T cell leukemia/lymphoma (ATL) and HTLV-seropositive controls, suggesting that these genes may be etiologically important in the development of ATL Using the U.S. HIV/AIDS Cancer Match Study, among 499,230 persons with HIV/AIDS, the risk of in situ and invasive cancers of the anus, cervix, oropharynx, penis, vagina, and vulva was significantly higher among persons with AIDS compared to the general population. During the highly active antiretroviral therapy (HAART) era (1996-2004), a low CD4 T-cell count was associated with increased risk of invasive anal cancer, invasive cervical cancer, and in situ vagina or vulva cancers. Among men, incidence of in situ and invasive anal cancer was significantly higher during 1996-2004 than 1990-1995 (61% increase for in situ cancers and 104% increase for invasive cancers). Incidence of other cancers was stable over time. These results show that HPV-associated cancer risk is increased among persons with AIDS and rises with increasing immunosuppression. The increasing anal cancer incidence during the HAART era indicates that prolonged survival may be associated with increased risk of certain HPV-associated cancers. In a study of cancer risk in the 4-27 month period following AIDS diagnosis, KS incidence was lower in 1996-2002 (335/ 100,000 person-years) than in 1990-1995 (1839/100,000 person-years), NHL incidence pattern was similar (i.e., 390/100,000 person-years in 1996-2002 and 1066/100,000 person-years in 1990-1995). In 1996-2002, for each decline in CD4 cell count of 50 cells per microliter of blood, KS risk increased by 40%, central nervous system non-Hodgkin lymphoma subtypes by 85%, diffuse large B-cell lymphoma 12%, but n increases were demonstrable for Burkitt lymphoma . Kaposi sarcoma (RR = 0.22, 95% CI = 0.20 to 0.24) and for non-Hodgkin lymphoma (RR = 0.40, 95% CI = 0.36 to 0.44) risks were lower in the period of 1996-2002 than in 1990-1995. In persons with HIV/AIDS (PWHAs), the risk of Hodgkin lymphoma (HL) 4 through 27 months after AIDS onset was significantly higher in 1996 to 2002 than earlier. The incidence in PWAs with 150 to 199 CD4 cells/muL was 53.7 per 10(5) py's, whereas in PWAs with fewer than 50 CD4 cells/muL, it was 20.7 per 10(5) py's (P(trend) = .002). For each HL subtype, incidence decreased with declining CD4 counts, but nodular sclerosing decreased more precipitously than mixed cellularity, thereby increasing the proportion of mixed cellularity HL seen in PWAs. The extent standardized incidence ratio (SIR) may underestimate relative risk (RR) of cancer risk among people with HIV/AIDS (PWHA) in registry-based was investigated using the 3 AIDS-related cancers: KS, central nervous system non-Hodgkin lymphoma (CNS NHL) and cervical cancer. SIRs substantially underestimate RRs for KS and CNS NHL, likely from the exceptionally high relative risk of KS and CNS NHL among PWHA. We measured serum levels in 360 HIV-1-infected individuals of soluble CD23 (sCD23), sCD27, sCD30, interleukin (IL)-6, IL-10, total immunoglobulin E, C-reactive protein, and Epstein-Barr virus DNA load, and genotyped 38 single nucleotide polymorphisms (SNPs) in candidate genes. We used principal component (PC) analysis to summarize inter-individual and longitudinal variation in the serum markers and generalized estimating equations to model the relationship between the first PC and the 38 SNPs. Ten SNP associations with serum levels were statistically significant, of which the strongest were IL13-1112C>T with sCD30, CC chemokine ligand 5 (CCL5)-403G>A with sCD23, and CXC chemokine ligand 12 (CXCL12)+535G>A with IL-10 (all p<0.01). Higher values of the serum marker first PC were associated with CCL5-403A and lower values were related to IL13-1112T. These findings suggest mixed genetic influences on Th2 markers overall, and discordance of Th2 polarization of circulating T-cells and serum levels in HIV-infected subjects. Using samples from the KS clonality and gene expression study, we showed that HHV8 load in cross-sectional peripheral blood was associated with KS progression and, to a lesser extent, with KS burden. Other correlates include low hemoglobin and low platelets. Collaborations with private and academic laboratories were established to foster development of detection methods for known or possible cancer-associated viruses.